This invention relates to methods and apparatus for in vivo measurement of carbon monoxide concentration in the exhaled breath of a patient. More particularly, the invention relates to a method and apparatus for direct measurement of the carbon monoxide production rate of a patient.
It is known that hemoglobin, myoglobin, and a series of heme enzymes, which reside principally in the liver, are the major hemoproteins. It is also well known that the end products of the catabolism of the heme moiety of these compounds are (1) iron, which is conserved, (2) carbon monoxide (CO), which is normally excreted in the breath, and (3) bilirubin, which is excreted by the liver and chemically modified in the gastrointestinal tract to a series of urobilins.
The principal source of CO and of bilirubinxe2x80x94each a surrogate for the otherxe2x80x94is from the catabolism of circulating red cells at the end of their life span. A small portion of CO is also derived from cytoplasmic hemoglobin released as a shroud during enucleation of normoblasts and from aborted red blood cell precursors that never reach the peripheral blood (i.e., ineffective erythropiesis).
The rate of CO excretion (or production) is thus clinically significant. For example, in patents with hemolytic anemias, hematologists need a measure of the effectiveness of therapy. Usually they rely principally on an increase in the hematocrit or a decrease in the reticulocyte count. An increase in hematocrit is comparatively slow, whereas a decrease in reticulocyte count is more rapid.
It is likely that if treatment were effective very rapidly (i.e., instantaneously) it would take 5 to 7 days for the reticulocyte count to decrease to normal levels because of maturing red cell precursors already in the formative-stage pipeline in the bone marrow. Moreover, reticulocyte levels may be altered by intercurrent conditions such as inflammation and infections.
By contrast, the rate of carbon monoxide excretion typically decreases rapidly to normal levels within hours and will more accurately reflect hemolytic rates, as would the plasma unconjugated bilirubin concentration.
Carbon monoxide excretion has two (2) distinct components. The first represents endogeneous production of CO. The second accrues from exogeneous CO absorbed from the atmosphere, both in smokers and non-smokers.
Various non-invasive methods (and apparatus) have been employed to determine the concentration of carbon monoxide in the breath. One method includes incrementally acquiring a sample of xe2x80x9cend-tidalxe2x80x9d breath and analyzing the acquired sample by mass spectroscopy or gas chromatography to determine the end-tidal carbon monoxide concentration. The sample is obtained by extracting from each of several successive breaths a portion of the apparent end-tidal breath using a syringe. The end-tidal portion of breath is determined by observing the chest movements of the infant. See, e.g., Vreman et al., U.S. Pat. No. 4,831,024.
A major drawback with this method is that the results merely provide an estimate of the carbon monoxide concentration, not the rate of carbon monoxide production.
A further problem with this method is that accurate assessment of the concentration difference in carbon monoxide requires obtaining good samples of end-tidal patient breath. This essentially requires that the patient have a regular, predictable breathing cycle. Thus, it can be difficult to obtain a good sample by watching chest wall movement, particularly for a newborn and for patients having irregular breathing cycles.
In U.S. Pat. No. 5,293,875 further methods and apparatus are disclosed for measuring the end-tidal carbon monoxide concentration in a patient""s breath. The method comprises measuring the room carbon monoxide concentration, end-tidal carbon dioxide concentration (ETCO2), the average carbon dioxide concentration, and the average carbon monoxide concentration in the patient""s breath. From this data, the apparatus computes the end-tidal carbon monoxide xe2x80x9cconcentrationxe2x80x9d corrected for room air and the index of CO/CO2.
A major drawback of the ""875 method is that the index of CO/CO2 is a derived parameter, which, according to the invention, xe2x80x9cmayxe2x80x9d relate the rate of carbon monoxide production to the degree of hemolysis. The apparatus is thus incapable of providing a direct measure of the carbon monoxide production rate.
Further, the apparatus employs a conventional electrochemical sensor. Such sensors are sensitive to many other gases such as hydrogen (H2), and are therefore susceptible to error.
It is well known that hydrogen is a waste product, emanating from the gastrointestinal system, which is also normally excreted in the breath. The hydrogen typically evolves from various digestive abnormalities, such as lactose intolerance, or the inability to thoroughly digest the carbohydrates and/or disaccharides contained in the system. When this occurs, bacteria will digest the noted substances and give off hydrogen as a bi-product.
Another problem with conventional sensors is that the measurement dynamics of the sample gas transport through the gas permeable membrane and oxidation-reduction in the electrochemical cell results in a relatively slow response time such that discrete samples of the end-tidal breath must be obtained and analyzed to determine the end-tidal carbon monoxide concentration.
It is therefore an object of the present invention to provide an improved method and apparatus for the in vivo measurement of carbon monoxide production rate.
It is another object of the invention to provide a method and apparatus for xe2x80x9cdirectxe2x80x9d, rapid, real-time assessment of the level of hemolysis in the blood.
It is yet another object of the invention to provide a method and apparatus for assessment of carbon monoxide production rate that substantially reduces the errors associated with the H2 excretion.
In accordance with the above objects and those that will be mentioned and will become apparent below, the apparatus for in vivo measurement of carbon monoxide production rate in accordance with this invention comprises a first gas detector for detecting the concentration of a first selected gas in at least first and second gas samples, the first gas detector being adapted to provide output signals corresponding to the first selected gas concentration in the first and second gas samples; a second gas detector adapted to substantially simultaneously detect the concentration of at least second and third selected gases in the first and second gas samples, the second gas detector being further adapted to provide output signals corresponding to the second and third selected gas concentrations in the first and second gas samples; means for providing the first and second gas samples to the first and second gas detectors; and processing means for determining the rate of carbon monoxide production in at least the second sample in response to the first and second gas detectors output signals.
The method of determining the carbon monoxide production rate in a subject in accordance with the invention comprises the steps of (a) introducing a room air sample to first and second gas detectors during a first period of time; (b) detecting the concentration of carbon dioxide in the room air sample (CO2) during the first period of time; (c) substantially simultaneously detecting the concentration of carbon monoxide in the room air sample (CO) and the concentration of hydrogen in the room air sample (H2) during the first period of time; (d) introducing a breath sample from the subject to the first and second gas detectors during a second period of time; (e) measuring the concentration of carbon dioxide in the breath sample (CO2xe2x80x2) during the second period of time; (f) substantially simultaneously measuring the concentration of carbon monoxide in the breath sample (COxe2x80x2) and the concentration of hydrogen in the breath sample (H2xe2x80x2) during the second period of time; (g) comparing the CO2xe2x80x2, COxe2x80x2, and H2xe2x80x2 detected in the breath sample to the CO2, CO and H2 detected in the room air sample to derive corrected carbon dioxide (CO2xe2x80x3), carbon monoxide (COxe2x80x3) and hydrogen (H2xe2x80x3) values; and (h) determining the carbon monoxide production rate ({dot over (V)}CO) from the following relationship:   VCO  =            ∫              t        1                    t        0              ⁢                  CO        xe2x80x3            ⁢              ⅆ        t            
where:
t1-t0=the second period of time